Brain damage after cerebral ischemia continues to be a clinical challenge that has proven to be resistant to most therapies that have been tested in humans. The overall objective of the proposed research is to discover the most appropriate genes for subsequent development of single and multifacet gene and drug therapies. Studying patients sustaining a stereotypical ischemic challenge during aortic arch surgery with deep hypothermic circulatory arrest (DHCA) and incomplete retrograde cerebral perfusion (RCP);our specific aims are to test the following hypotheses: H1. Polymorphisms in candidate genes associated with neuroprotection, neurotoxicity, and Alzheimer's disease will predict extent of brain injury after ischemia. Three pathophysiologically based genotypes, apolipoprotein E (ApoE), heat shock protein (HSP), and myeloperoxidase(MPO), all with prior evidence of an effect in vulnerability to brain ischemia, will be evaluated for contribution to six quantitative indicators of acute neural injury after DHCA with RCP (S-1002, NSE, hyperphospho-neurofilament H, hypophospho-neurofilament H, dephospho- neurofilament H, and a calpain-derived N-terminal fragment of alpha-spectrin). H2. Polymorphisms in genes associated with most known major mechanisms in the pathophysiology of brain damage after ischemia will affect outcome. In an exercise in relevant gene discovery, 91 pathophysiologically based genotypes will be examined for possible contribution to a quantitative indicator (the same six biomarkers as in H1) of acute neural injury after DHCA with RCP. For each specific aim quantitative indicators of acute neural injury will include the known biochemical markers of brain damage from brain inflow and RCP effluent blood and venous blood after surgery. Two hundred DHCA patients will be enrolled. Information derived from this setting about genomic vulnerability will not only lead to changes in approach to management of such patients during surgery, but also, and perhaps more importantly, will generate information that will be of use in many non- operative settings associated with global brain ischemia and stroke. As stroke is the third leading cause of death and leading cause of disability in the United States, the impact of this research may be very significant, possibly leading to gene or new drug or gene therapy of stroke or other brain ischemia syndromes. PUBLIC HEALTH RELEVANCE: The operating room environment provides a unique opportunity for study of genomic variation in ischemic vulnerability, as more or less stereotypical incomplete cerebral ischemia occurs fairly predictably. Such information derived from this setting about genomic vulnerability will not only lead to changes in approach to management of such patients during surgery, but also, and perhaps more importantly, will generate information that will be of use in many non-operative settings associated with global brain ischemia and stroke. As stroke is the third leading cause of death and leading cause of disability in the United States, the impact of this research may be very significant, possibly leading to gene or new drug therapy of stroke or other brain ischemia syndromes.